The molecular and cellular pathophysiology of the sickle cell syndromes are now appreciated with a great deal of precision. On the other hand, our understanding of the relationship of these subcellular events to the variable clinical expression of sickle cell disease remains largely speculative. A major effort of our research group has been to develop quantitative ways to clarify disease pathogenesis, as well as to assess severity and progression. Using calibrated phthalate ester separation method, which we previously described, we have now defined at least three cellular processes contributing to the extensive red cell heterogeneity that is commonly observed in the sickle cell syndromes. Using a sensitive nickel mesh filtration system, we are systematically determining the effects of changes in oxygen saturation, corpuscular hemoglobin concentration/composition and temperature of the flow properties of sickle hemoglobin containing erythrocytes. Ophthalmological studies of the patients show highly significant correlations between the extend of erythrocyte heterogeneity with conjunctival and retinal vessel pathology. As predicted by biophysical studies of polymer formation, we find that treatment of steady state sickle cell.patients with selective arteriolar vasodilators results in a significant resolution of both acute conjunctival and retinal abnormalities, as well as an improvement in color vision performance. These beneficial effects occurred in the absence of a direct drug-induced inhibition of polymer formation, and therefore suggests that inappropriate vasospasm or frank vasoconstriction, perhaps in response to the altered rheology of red cell containing polymerized sickle hemoglobin is a significant contributing factor to the pathogenesis of sickle cell disease. This conclusion is also supported by our recent observation that "relative" hypertension is a significant risk factor for the occurrence of stroke in sickle cell patients. Using the technique of laser-Doppler velocimetry, and phlethysmography we have found that forearm cutaneous microcirculatory flow is sickle cell individuals show characteristic patterns, which may become more "normalized" depending upon the fraction of non-S hemoglobins and during crisis. We hope that these cellular and physiological measurements will allow us to understand better the extreme spectrum of disease manifestations.